Azilect

The pharmacokinetic profile of rasagiline is similar in men and women.

For the comparison between rasagiline 1 mg/day and placebo, no differences in effectiveness based on age or gender were detected.

In addition in the TEMPO study the following secondary measurements of effectiveness were statistically significant and the effects of AZILECT 1 mg tablets over placebo are presented below: UPDRS ADL (Activities of Daily Living) subscale score (p=0.0003); UPDRS Motor subscale score (p<0.0001).

In phase II/III premarketing trials approximately 1361 patients received AZILECT with 771 being treated for at least one year, approximately 361 patients treated for at least two years, and 245 receiving AZILECT for more than 3 years.

The effectiveness of AZILECT for the treatment of Parkinson's disease was established in three 18- to 26-week, randomized, placebo-controlled trials. In one of these trials study TVP-1012/232 (TEMPO) AZILECT was given as initial monotherapy treatment and in the other two studies as adjunctive therapy to levodopa TVP-1012/133 (PRESTO) and TVP-1012/122 (LARGO).

Following repeat dose administration (7 days) of rasagiline (1 mg/day) in subjects with mild hepatic impairment (Child-Pugh score 5-6), AUC and C_max were increased by 2 fold and 1.4 fold, respectively, compared to healthy subjects. In subjects with moderate hepatic impairment (Child-Pugh score 7-9), AUC and C_max were increased by 7 fold and 2 fold, respectively, compared to healthy subjects. (See Warnings, Hepatic Insufficiency and Dosage, Patients with Hepatic Impairment.)

AZILECT (rasagiline mesylate tablets) is an irreversible, monoamine oxidase inhibitor indicated for the treatment of idiopathic Parkinson's disease. AZILECT inhibits MAO type B, but adequate studies to establish whether rasagiline is selective for MAO type B (MAO-B) in humans have not yet been conducted. MAO, a flavin-containing enzyme, is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. MAO-B is the major form in the human brain. In ex vivo animal studies in brain, liver and intestinal tissues rasagiline was shown to be a potent, irreversible monoamine oxidase type B (MAO-B) selective inhibitor. Rasagiline at the recommended therapeutic dose was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The dose at which rasagiline selectively inhibits only MAO-B (and not MAO-A) in humans and the sensitivity to tyramine during rasagiline treatment at doses higher than 1 mg have not been sufficiently characterized (see Precautions).

The precise mechanisms of action of rasagiline are unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction.

Studies in healthy subjects and in Parkinson's disease patients have shown that rasagiline inhibits platelet MAO-B irreversibly. The inhibition lasts at least 1 week after last dose. Almost 25-35 % MAO-B inhibition was achieved after a single rasagiline dose of 1 mg/day and more than 55% of MAO-B inhibition was achieved after a single rasagiline dose of 2 mg/day. Over 90% inhibition was achieved 3 days after rasagiline daily dosing at 2 mg/day and this inhibition level was maintained 3 days post-dose. Multiple doses of rasagiline of 0.5, 1 and 2 mg per day resulted in complete MAO-B inhibition.

No additional in vivo trials have investigated the effect of AZILECT on other drugs metabolized by the cytochrome P450 enzyme system. In vitro, studies showed that rasagiline at a concentration of 1 µg/ml (equivalent to a level that is 160 times the average C_max ~5.9-8.5 ng/mL in Parkinson's disease patients after 1 mg rasagiline multiple dosing, did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results indicate that rasagiline is unlikely to cause any clinically significant interference with substrates of these enzymes.

Conclusive data are not available for renally impaired patients. As unconjugated rasagiline is not excreted by the kidney, rasagiline can be given at usual doses in patients with mild renal impairment. Due to the absence of adequate safety data, rasagiline should not be administered to patients with moderate to severe renal impairment.

When ciprofloxacin, an inhibitor of CYP 1A2, was administered to healthy volunteers (n=12) at 500 mg (BID) with 2 mg/day rasagiline, the AUC of rasagiline increased by 83% and there was no change in the elimination half life. (See Warnings, Ciprofloxacin and Other CYP1A2 Inhibitors and Dosage, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors.)

AZILECT has not been investigated in patients below 18 years of age.

Severe CNS toxicity associated with hyperpyrexia and death has been reported with the combination of tricyclic or tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) and non-selective MAOIs or selective MAO-B inhibitors. Therefore, the coadministration of antidepressants with rasagiline is contraindicated (see Contraindications).

Co-administration of rasagiline 1 mg/day and theophylline, a substrate of CYP 1A2, up to 500 mg twice daily to healthy subjects (n=24), did not affect the pharmacokinetics of either drug.

Data from population pharmacokinetic studies comparing rasagiline clearance in the presence and absence of levodopa have given conflicting results. Although there may be some increase in rasagiline blood levels in the presence of levodopa, the effect is modest and rasagiline dosing need not be modified in the presence of levodopa.

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylation to yield: 1-aminoindan (AI), 3-hydroxy-N-propargyl-1-aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In vitro experiments indicate that both routes of rasagiline metabolism are dependent on cytochrome P450 (CYP) system, with CYP 1A2 being the major iso-enzyme involved in rasagiline metabolism. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway.

After oral administration of ¹⁴C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

Since age has little influence on rasagiline pharmacokinetics, it can be administered at the recommended dose in the elderly.

The safety and effectiveness of AZILECT in patients below 18 years of age have not been established.

Reproductive studies conducted with rasagiline in animals did not reveal any negative effect at doses much higher than those used in the clinical studies. However, there are no adequate and well-controlled studies of rasagiline in pregnant women. Because animal reproduction studies are not always predictive of human response, AZILECT should be used during pregnancy only if clearly needed.

When used as monotherapy, postural hypotension was reported in approximately 3% of patients treated with 1 mg rasagiline and 5% of patients treated with placebo. In the monotherapy trial, postural hypotension did not lead to drug discontinuation and premature withdrawal in the rasagiline treated patients or the placebo treated patients.

When used as an adjunct to levodopa, postural hypotension was reported in approximately 6% of patients treated with 0.5 mg rasagiline, 9% of patients treated with 1 mg rasagiline and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with rasagiline 1 mg/day, no patients treated with rasagiline 0.5 mg/day and no placebo-treated patients.

Clinical trial data suggest that postural hypotension occurs most frequently in the first two months of rasagiline treatment and tends to decrease over time.

Concomitant use of SSRI, tricyclic, and tetracyclic antidepressants with AZILECT is contraindicated (see Contraindications).

AZILECT should not be administered along with other MAO inhibitors, including reversible MAOI (moclobemide) and selective MAO-B inhibitors (selegiline) because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis (see Contraindications).

Serious, sometimes fatal reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors (see Contraindications).

Approximately half of patients in clinical trials were 65 years and over. There were no significant differences in the safety profile of the geriatric and non-geriatric patients.

The concomitant use of AZILECT and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the administration of sympathomimetics and non-selective MAO inhibitors. One case of hypertensive crisis has been reported in a patient taking the recommended doses of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine). Therefore, in view of AZILECT's MAO inhibitory activity, AZILECT should not be used concomitantly with sympathomimetics including nasal and oral decongestants and cold remedies (see Contraindications).

(See Pharmacology, Drug Interactions and Precautions, General, Dyskinesia Due to Levodopa Treatment.)

Experimental data indicated that rasagiline inhibits prolactin secretion and, thus, may inhibit lactation. It is not known whether rasagiline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AZILECT is administered to a nursing woman.

Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using AZILECT for any indication. Ideally periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).

Conclusive data are not available for renally impaired patients. As unconjugated rasagiline is not excreted by the kidney, rasagiline can be given at usual doses in patients with mild renal impairment. Due to the absence of adequate safety data, rasagiline should not be administered to patients with moderate to severe renal impairment.

Rasagiline plasma concentrations may increase up to 2-fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. This could result in increased adverse events. (See Pharmacology, Drug Interactions and Warnings, Ciprofloxacin and Other CYP1A2 Inhibitors.)

Rasagiline should not be used at daily doses exceeding the maximum recommended (1 mg/day) because of the risks associated with nonselective inhibition of MAO. Adequate studies above this dose have not been conducted. Therefore, if rasagiline is to be used without restrictions being placed on diet and concomitant drug use, it is critical to adhere to this maximum dose.

(See Pharmacology, Drug Interactions.)

When used as an adjunct to levodopa AZILECT may potentiate dopaminergic side effects and exacerbate pre-existing dyskinesia (treatment-emergent dyskinesia occurred in about 18% of patients treated with 0.5 mg or 1 mg rasagiline as an adjunct to levodopa and 10% of patients who received placebo as an adjunct to levodopa). Decreasing the dose of levodopa may ameliorate this side effect.

No specific laboratory tests are necessary for the management of patients on AZILECT.

In the monotherapy study, hallucinations were reported as an adverse event in 1.3% of patients treated with 1 mg rasagiline and in 0.7% of patients treated with placebo. In the monotherapy trial, hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 1.3% of the 1 mg rasagiline treated patients and in none of the placebo treated patients.

When used as an adjunct to levodopa, hallucinations were reported as an adverse event in approximately 5% of patients treated with 0.5 mg/day, 4% of patients treated with 1 mg/day rasagiline and 3% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of patients treated with 0.5 mg/day or 1 mg/day and none of the placebo treated patients.

Patients should be cautioned of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop.

The concomitant use of AZILECT and dextromethorphan was not allowed in clinical studies. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of AZILECT's MAO inhibitory activity, dextromethorphan should not be used concomitantly with AZILECT (see Contraindications).

The risk of exceeding the recommended daily dose (1 mg/day) should be explained. The explanation should describe the signs and symptoms associated with MAOI induced hypertensive reactions. Patients should be urged to immediately report any severe headache or other atypical or unusual symptoms not previously experienced.

Patients should be advised to inform their physician if they are taking, or planning to take, any prescription or over-the-counter drugs especially with antidepressants and over-the-counter cold medications since there is a potential for interaction with AZILECT. Patients should not use meperidine with AZILECT.

Patients taking AZILECT as adjunct to levodopa should be advised there is the possibility of increased dyskinesia and postural hypotension.

Patients are advised to monitor for melanomas frequently and on a regular basis. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).

Patients should be instructed to take AZILECT as prescribed. If a dose is missed the next dose should be taken at the usual time on the following day. The patient should not double-up the dose of AZILECT.

Each white to off-white, round, flat, beveled tablet, debossed with “GIL” and “1” below on one side and plain on the other, contains: rasagiline 1 mg, as mesylate. Nonmedicinal ingredients: colloidal silicon dioxide, mannitol, pregelatinized starch, starch, stearic acid and talc. Bottles of 30. Store at 25°C with excursions permitted to 15-30°C.

Each white to off-white, round, flat, beveled tablet, debossed with “GIL” and “0.5” below on one side and plain on the other, contains: rasagiline 0.5 mg, as mesylate. Nonmedicinal ingredients: colloidal silicon dioxide, mannitol, pregelatinized starch, starch, stearic acid and talc. Bottles of 30. Store at 25°C with excursions permitted to 15-30°C.

AZILECT should not be administered along with antidepressants. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with a tricyclic, tetracyclic, SSRI, or SNRI antidepressant. Similarly, at least 14 days should elapse after discontinuing treatment with a tricyclic, tetracyclic, SSRI, or SNRI antidepressant before starting AZILECT. Because of the long half-lives of fluoxetine and its active metabolite, at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of AZILECT (see Warnings).

As with other MAOIs, patients taking AZILECT should not undergo elective surgery requiring general anesthesia. Also, they should not be given local anesthesia containing cocaine or sympathomimetic vasoconstrictors. AZILECT should be discontinued at least 14 days prior to elective surgery. If surgery is necessary sooner, benzodiazepines, mivacurium, fentanyl, morphine, and codeine may be used cautiously.

AZILECT should not be used with the antitussive agent dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. AZILECT is also contraindicated for use with St. John's wort, and cyclobenzaprine (a tricyclic muscle relaxant).

Like other MAOIs, AZILECT is contraindicated for use with sympathomimetic amines, including amphetamines as well as cold products and weight-reducing preparations that contain vasoconstrictors (e.g., pseudoephedrine, phenylephrine and ephedrine). Severe hypertensive reactions have followed the administrations of sympathomimetics and non-selective MAO inhibitors. At least one case of hypertensive crisis has been reported in a patient taking the recommended doses of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine).

AZILECT is contraindicated for use with meperidine. Serious reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors. These reactions have been characterized by coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse and death. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with meperidine.

For similar reasons, AZILECT should not be administered with the analgesic agents tramadol, methadone, and propoxyphene.

As with other MAOIs, AZILECT is contraindicated in patients with pheochromocytoma.

AZILECT should not be administered along with other MAO inhibitors because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with MAO inhibitors.

AZILECT plasma concentration may increase in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe hepatic Child-Pugh score 10-15) impairment. Patients with mild hepatic impairment should be given the dose of 0.5 mg/day. AZILECT should not be used in patients with moderate or severe hepatic impairment (see Pharmacology, Population Pharmacokinetics).

Severe CNS toxicity associated with hyperpyrexia and death has been reported with the combination of tricyclic or tetracyclic antidepressants, non-selective MAOIs (NARDIL, PARNATE) including the reversible MAOI, moclobemide and a selective MAO-B inhibitor, selegiline. These adverse events have included behavioral and mental status changes, diaphoresis, muscular rigidity, hypertension, syncope and death.

Serious, sometimes fatal, reactions with signs and symptoms including hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes progressing to extreme agitation, delirium, and coma have been reported in patients receiving a combination of selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (PROZAC), fluvoxamine (LUVOX) sertraline (ZOLOFT), and paroxetine (PAXIL), non-selective MAOIs, including the reversible MAOI moclobemide, or the selective MAO-B inhibitor selegiline. Similar reactions have been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs).

At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with a tricyclic, tetracyclic, SSRI, or SNRI antidepressant. Similarly, at least 14 days should elapse after discontinuing treatment with a tricyclic, tetracyclic, SSRI, or SNRI antidepressant before starting AZILECT. Because of the long half-lives of fluoxetine and its active metabolite, at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of AZILECT (see Contraindications).

Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. (See Pharmacology, Drug Interactions and Dosage, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors.)

Frequent: gastrointestinal hemorrhage. Infrequent: colitis, esophageal ulcer, esophagitis, fecal incontinence, intestinal obstruction, mouth ulceration, stomach ulcer, stomatitis, tongue edema. Rare: hematemesis, hemorrhagic gastritis, intestinal perforation, intestinal stenosis, jaundice, large intestine perforation, megacolon, melena.

In a double-blind, placebo-controlled trial (PRESTO) conducted in patients treated with AZILECT as adjunct to levodopa therapy, approximately 9% of the 164 patients treated with AZILECT 0.5 mg/day and 7% of the 149 patients treated with AZILECT 1 mg/day discontinued treatment due to adverse events compared to 6% of the 159 patients who received placebo. The AEs that led to discontinuation of more than one rasagiline treated patient were diarrhea, weight loss, hallucination, and rash. Adverse event reporting was considered more reliable for PRESTO than for the second controlled trial (LARGO); therefore only the adverse event data from PRESTO are presented in this section of labeling.

Infrequent: blepharitis, deafness, diplopia, eye hemorrhage, eye pain, glaucoma, keratitis, ptosis, retinal degeneration, taste perversion, visual field defect. Rare: blindness, parosmia, photophobia, retinal detachment, retinal hemorrhage, strabismus, taste loss, vestibular disorder.

Infrequent: hypocalcemia.

Infrequent: eczema, urticaria. Rare: exfoliative dermatitis, leukoderma.

Infrequent: bone necrosis, muscle atrophy. Rare: arthrosis.

Several of the more common adverse events seemed dose-related, including weight loss, postural hypotension, and dry mouth.

Other events of potential clinical importance reported in PRESTO by 1% or more of patients treated with rasagiline 1 mg/day as adjunct to levodopa therapy and at least as frequent as in the placebo group, in descending order of frequency include: skin carcinoma, anemia, albuminuria, amnesia, arthritis, bursitis, cerebrovascular accident, confusion, dysphagia, epistaxis, leg cramps, pruritus, skin ulcer.

There were no significant differences in the safety profile based on age or gender.

Other events of potential clinical importance reported by 1% or more of Parkinson's disease patients receiving AZILECT as monotherapy, and at least as frequent as in the placebo group, in descending order of frequency include: dizziness, diarrhea, chest pain, albuminuria, allergic reaction, alopecia, angina pectoris, anorexia, asthma, hallucinations, impotence, leukopenia, libido decreased, liver function tests abnormal, skin carcinoma, syncope, vesiculobullous rash, vomiting.

There were no significant differences in the safety profile based on age or gender.

Frequent: asthenia. Infrequent: chills, face edema, flank pain, photosensitivity reaction.

Infrequent: macrocytic anemia. Rare: purpura, thrombocythemia.

Frequent: bundle branch block. Infrequent: deep thrombophlebitis, heart failure, migraine, myocardial infarct, phlebitis, ventricular tachycardia. Rare: arterial thrombosis, atrial arrhythmia, AV block complete, AV block second degree, bigeminy, cerebral hemorrhage, cerebral ischemia, ventricular fibrillation.

Frequent: abnormal gait, anxiety, hyperkinesia, hypertonia, neuropathy, tremor. Infrequent: agitation, aphasia, circumoral paresthesia, convulsion, delusions, dementia, dysarthria, dysautonomia, dysesthesia, emotional lability, facial paralysis, foot drop, hemiplegia, hypesthesia, incoordination, manic reaction, myoclonus, neuritis, neurosis, paranoid reaction, personality disorder, psychosis, wrist drop. Rare: apathy, delirium, hostility, manic depressive reaction, myelitis, neuralgia, psychotic depression, stupor.

Frequent: hematuria, urinary incontinence. Infrequent: acute kidney failure, dysmenorrhea, dysuria, kidney calculus, nocturia, polyuria, scrotal edema, sexual function abnormal, urinary retention, urination impaired, vaginal hemorrhage, vaginal moniliasis, vaginitis. Rare: abnormal ejaculation, amenorrhea, anuria, epididymitis, gynecomastia, hydroureter, leukorrhea, priapism.

Rasagiline was administered to approximately 1361 patients during all PD phase II/III clinical trials. About 771 patients received rasagiline for at least one year, approximately 361 patients received rasagiline for at least two years and 245 patients received rasagiline for more than 3 years, with 138 patients treated for more than 5 years. The long-term safety profile was similar to that observed with shorter duration exposure.

The frequencies listed below represent the proportion of the 1361 individuals exposed to rasagiline who experienced events of the type cited.

All events that occurred at least twice (or once for serious or potentially serious events) except those already listed above, trivial events, terms too vague to be meaningful, adverse events with no plausible relation to treatment and events that would be expected in patients of the age studied were reported without regard to determination of a causal relationship to rasagiline.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients, infrequent adverse events are defined as those occurring in less than 1/100 to at least 1/1000 patients and rare adverse events are defined as those occurring in fewer than 1/1000 patients.

Frequent: cough increased. Infrequent: apnea, emphysema, laryngismus, pleural effusion, pneumothorax. Rare: interstitial pneumonia, larynx edema, lung fibrosis.

Symptoms of overdosage, although never observed with rasagiline during clinical development, may resemble those observed with non-selective MAO inhibitors.

Although no cases of overdose have been observed with rasagiline, the following description of presenting symptoms and clinical course is based upon overdose descriptions of non-selective MAO inhibitors.

Characteristically, signs and symptoms of non-selective MAOI overdose may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly, the peak intensity of the syndrome may not be reached for upwards of a day following the overdose. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring for a period of at least two days following the ingestion of such drugs in overdose, is strongly recommended.

The clinical picture of MAOI overdose varies considerably; its severity may be a function of the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved.

Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.

There is no specific antidote for rasagiline overdose. The following suggestions are offered based upon the assumption that rasagiline overdose may be modeled after non-selective MAO inhibitor poisoning. Treatment of overdose with non-selective MAO inhibitors is symptomatic and supportive. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential.

A poison control center should be called for the most current treatment guidelines.

AZILECT plasma concentration will increase in patients with hepatic impairment. Patients with mild hepatic impairment AZILECT should use 0.5 mg daily of AZILECT. AZILECT should not be used in patients with moderate to severe hepatic impairment. (See Pharmacology, Population Pharmacokinetics, Hepatic Insufficiency and Warnings, Hepatic Insufficiency.)

The dosage of AZILECT shown to be effective in controlled clinical trials for adjunct therapy was 0.5-1 mg once daily. The recommended initial dose is 0.5 mg administered once daily. If a sufficient clinical response is not achieved, the dose may be increased to 1 mg administered once daily.

The recommended and maximum dose in both monotherapy and adjunct therapy is 1 mg once daily.

There is no evidence that additional benefit will be obtained from the administration of doses higher than that recommended. Furthermore, higher doses will likely result in a loss of selectivity of rasagiline towards MAO-B with an increase in the inhibition of MAO-A. There is an increased risk of adverse reactions with higher doses as well as an increased risk of hypertensive episode (“cheese reaction”).

Rasagiline plasma concentrations are expected to double in patients taking concomitant ciprofloxacin and other CYP1A2 inhibitors. Therefore, patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should use 0.5 mg daily of AZILECT (see Pharmacology, Drug Interactions, Ciprofloxacin and Effect of Other Drugs on the Metabolism of AZILECT and Warnings, Ciprofloxacin and Other CYP1A2 Inhibitors).

When AZILECT is used in combination with levodopa a reduction of the levodopa dosage may be considered based upon individual response. During the controlled trials of AZILECT as adjunct therapy to levodopa, levodopa dosage was reduced in some patients. In clinical studies, dosage reduction of levodopa was allowed within the first 6 weeks if dopaminergic side effects, including dyskinesia and hallucinations, emerged. In the PRESTO study levodopa dosage reduction occurred in 8 % of patients in the placebo group and in 16 % and 17 % of patients in the 0.5 mg/day and 1 mg/day rasagiline groups, respectively. In those patients who had levodopa dosage reduced, the dose was reduced on average by about 7 %, 9%, and 13 % in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In the LARGO study levodopa dosage reduction occurred in 6 % of patients in the placebo group and in 9 % in the rasagiline 1 mg/day group. In patients who had their levodopa dosage reduced, the dose was reduced on average by about 13% and 11 % in the placebo and the rasagiline groups, respectively.

The recommended AZILECT dose for the treatment of Parkinson's disease patients is 1 mg administered once daily.

Conclusive data are not available for renally impaired patients. As unconjugated rasagiline is not excreted by the kidney, rasagiline can be given at usual doses in patients with mild renal impairment. Due to the absence of adequate safety data, rasagiline should not be administered to patients with moderate to severe renal impairment.

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